Procoagulant changes in fibrin clot structure in patients with cirrhosis are associated with oxidative modifications of fibrinogen

Abstract

To cite this article: Hugenholtz GCG, Macrae F, Adelmeijer J, Dulfer S, Porte RJ, Lisman T, Ari€ ens RAS. Procoagulant changes in fibrin clot structure in patients with cirrhosis are associated with oxidative modifications of fibrinogen. J Thromb Haemost 2016; 14: 1054-66. Essentials Patients with cirrhosis have hemostatic changes, which may contribute to a risk of thrombosis. This in vitro study compares clot formation and structure between patients and healthy subjects. Clot formation is delayed in patients; ultimately, however , clot permeability is decreased. The thrombogenic structure of fibrin clots may contribute to the thrombotic risk in cirrhosis. Abstract. Background and Objectives: Patients with cirrho-sis can be at risk of thrombotic complications due to an imbalance between hemostatic components. However, little is known on how the disease affects clot generation or how alterations in the structure of fibrin clots may affect the hemostatic function of these patients. Methods: We investigated the formation and structure of clots generated with plasma and purified fibrinogen of 42 patients with cirrhosis. Clots generated with plasma and fibrino-gen of 29 healthy volunteers were studied for comparison. Clot formation and structure were assessed by turbidity, permeation studies, confocal laser and scanning electron microscopy (SEM). The extent of fibrinogen oxidation was assessed by measuring the carbonyl content of purified fibrinogen samples. Results: Tissue factor and throm-bin-induced clotting of plasma was delayed in patients. The clotting rate was also decreased, but change in tur-bidity, fibrin density and fiber thickness were largely comparable to healthy volunteers. Conversely, clot perme-ability was significantly decreased in patients. When clots were generated with purified fibrinogen, differences in clot formation and structure similar to those in plasma were found. The carbonyl content was increased in patient fibrinogen and correlated with disease severity and clot permeability. Conclusions: Delayed clot formation in cir-rhosis ultimately results in decreased clot permeability. Similar alterations in clots generated with purified fibrino-gen suggest that modifications of the molecule are (partly) responsible. Taken together, these findings are indicative of hypercoagulable features of clots of patients with cirrhosis, which may explain the increased risk of thrombosis associated with this condition.

Preserved hemostatic status in patients with non-alcoholic fatty liver disease

“…We have recently shown that fibrin clot permeability in patients with cirrhosis of varying etiology is markedly reduced despite decreased fibrinogen plasma levels in these patients. The procoagulant properties of the fibrin clot in cirrhosis was attributed to increased oxidation of the fibrinogen molecule [24], which is known to result in a more thrombogenic fibrin clot. The thrombogenic nature of fibrin clots in patients with NAFLD, as identified in the present study, is likely attributable to multiple factors including increased oxidation of the fibrinogen molecule and elevated plasma fibrinogen levels.…”

Coagulation Failure in Patients With Acute‐on‐Chronic Liver Failure and Decompensated Cirrhosis: Beyond the International Normalized Ratio

“…CT INT at admission was the only TE parameter that correlated with the development of bleeding events during hospitalization. The lack of association between hypocoagulable features on TE and the risk of bleeding observed in our study has also been reported by other authors and is probably due to the fact that portal hypertension constitutes the main pathogenic factor of bleeding events in cirrhosis. Hemostatic failure–related bleedings such as bruising, epistaxis, and gum bleeds are relatively infrequent and normally constitute minor events in the evolution of patients with decompensated cirrhosis.…”

Exposure of fibrinogen and thrombin to nitric oxide donor ProliNONOate affects fibrin clot properties

“…Fibrin fiber density of each images stack were determined as previously described by Hugenholtz et al [35]. Briefly, lines were placed across the slices at 10 μm increments and averaging number of fibers intersecting the line were recorded.…”